tbuckley/cabot-search huggingface dataset:
Molecular classification of endometrial cancer of Chinese population.
Authors: Nan Kang, Zhiqi Wang, Fei Gai, Wenqing Su, Danhua Shen, Jianliu Wang
Journal: Journal of Clinical Oncology (2022)

e17623 Background: Endometrial cancer (EC) is one of the most prevalent gynecologic tumors. Current diagnosis and treatment of EC no longer rely solely on traditional histopathological classification. Nevertheless, molecular classification of EC demonstrated clear prognostic value and may guide clinical decision. Methods: In this study, archived tissue specimens from 240 EC patients from Department of Pathology, Peking University People’s Hospital. Four subtypes [POLE ultramutated (POLE mut), microsatellite instability high (MSI-H), copy number low (CNL), and copy number high (CNH)] were stratified by next-generation sequencing (NGS) panel (Amoy Diagnostics, Xiamen, China) targeting POLE, TP53, BRCA1, and BRCA2 genes and microsatellite instability (MSI) status. Immunohistochemistry (IHC) was applied to detect the expression of P53, MMR and other related proteins. Results: Distribution of the EC subtypes in 240 patients was 13 (5.42%) of POLE mut, 36 (15.00%) of MSI-H, 41 (17.08%) of CNH, and 150 (62.50%) of CNL. Compared to published results of EC subtypes in Caucasian including TCGA, ProMisE as well as TransPORTEC, real-world data on Chinese ECs displayed a significantly larger proportion of CNL. In addition, novel biomarkers such as DUSP1, MCF7 and BUB1, which were independent prognostic marker from our previous research were validated. Also, it was found that BRCA2 appeared to be more prevalent in EC than BRCA1. Further analysis revealed that the overall consistency for NGS-based and IHC-based TP53 abnormalities detection and MSI/MMR status assessment were as high as 87.5% and 100%, respectively. Conclusions: Chinese ECs have unique molecular characteristics. In order to perform accurate molecular typing of Chinese ECs, more molecular indicators that match the characteristics of the Chinese population need to be added to the existing classifiers. NGS-based panel is easy to operate and replicate with high accuracy. Thus, it is a viable alternative to IHC in EC molecular classification.
NFB-20. Pre-clinical models of Mismatch Repair Deficient Gliomas
Authors: Ethan Putnam, Sridevi Yadavilli, Adam Dawood, Sean Mizoguchi, Bavani Subramaniam, Miriam Bornhorst, Javad Nazarian
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Lynch syndrome and Biallelic Mismatch Repair Deficiency (BMMRD) are hereditary tumor predisposition syndromes, resulting from one or two (respectively) germline alterations in DNA mis-match repair (MMR) genes. Currently, there are few treatments for mismatch repair deficient (MMRD) gliomas, in part due to a lack of suitable pre-clinical models for drug testing. The purpose of this study is to develop and characterize pre-clinical models of MMRD gliomas. METHODS: Primary cells were developed from patients diagnosed with MMRD gliomas and characterized through immunofluorescence staining (IF) for different cell type markers, western blot assays, and genome and transcriptome analysis. Murine models were generated through intracranial injection of mCherry-luciferase reporter expressing primary cells, and mice were monitored for evidence of engraftment and clinical symptoms. Drug screening on the cell lines was performed to identify potential therapeutic agents for in-vivo testing. RESULTS: The cell lines had similar characteristics as the primary glial tumors by IF staining and genome and transcriptome analysis. Adult NSG mice developed tumors around three weeks after intercranial transplantation of the tumor cells. These tumors closely resembled the primary patient tumors on histology. Preliminary drug testing on the cell lines showed efficacy of ONC201, ONC206, and RM006 against MMRD gliomas with IC50 concentrations of 1.77 μM, 185 nM, and 699 nM respectively. CONCLUSION: The generation of pre-clinical MMRD glioma models can lead to improved understanding of tumorigenesis, allowing for the identification of targetable molecules, and supporting novel treatment development.
Patient-derived explant model of appendiceal cancer.
Authors: Madeleine Cornelia Strach, Nicole Yeung, Hui-Ming Lin, Nabila Ansari, Cherry Koh, Joo-Shik Shin, James Kench, Margaret Centenera, Lisa Butler, Lisa Horvath, Kate Mahon
Journal: Journal of Clinical Oncology (2022)

4160 Background: Appendiceal cancers (AC) are rare with 5-year survival of 15% for high grade (HG) adenocarcinomas and 75% for low grade (LG) mucinous neoplasms. There is limited literature on the AC tumour microenvironment (TME) in disease progression and drug resistance. Ex vivo cultures, such as patient derived explants (PDEs), have been used for other solid tumours to test anticancer agents, explore the TME, and are being developed as personalised models. The aim of our study was to develop a PDE model of AC, preserve the TME, study the biological profile of AC and test novel therapies. Methods: Fresh tissue was collected during cytoreductive surgery (CRS) from consenting patients with AC with peritoneal disease, Jul 2020-Mar 2021. Tissues from 10 patients were dissected and cultured as PDEs under varying conditions of tissue size, media, matrix support and duration (Table). Uncultured Day 0 tissues and PDEs were fixed in formalin prior to paraffin embedding (FFPE). Immunohistochemical staining was performed on sections of FFPE tissue to assess viability with antibodies against the tumour marker, Cytokeratin-20 (CK20), and cell death marker, cleaved caspase 3 (CC3). Tissue architecture was rated on a 4-point scale (MS, J-SS). Cancer cells were counted in 6 Day 0 samples and PDEs from 3 patients using QuPath v0.3.2. Apoptotic index (AI) was calculated as the proportion of cells positive for CC3 divided by the number of total CK20 positive cells. Results: The mean proportion of tumour and mucin in the tissues was 3% (0-60%) and 39% (0-95%) respectively. Day 0 samples were viable with mean AI of cancer cells 7% (0-4%). Tissue architecture was maintained, as compared to Day 0 control, for varying sizes of PDE and culture durations up to 4d. More small or medium-sized PDEs had improved architecture compared to large sized PDEs (Table). PDEs at 4d had poorer architecture compared to at 1-3d. There was improved architecture in PDEs using enriched media with support factors compared to base media, and in specimens with matrix support compared to none. The mean AI of PDE cancer cells was 21% (0-92%) and 51% of PDEs had no cancer cell death. Conclusions: This is the first study demonstrating that AC tissue is amenable to ex vivo culture as PDEs. The optimal PDE model was &lt;10mm tissue placed on a gelatine sponge in enriched media for 1-3d. PDEs had preserved tissue architecture and viability compared to uncultured tissue. Protein expression was in keeping with the original tumour. We plan to use this model to test anticancer agents and explore the TME of AC.[Table: see text]
MODL-08. Cellular yield and xenograft creation from probe washing after stereotactic biopsy of deep-seated CNS tumors in children
Authors: Michael DeCuypere, Sophie Xiao, Yuchen Du, Sandi Lam, Xiao-Nan Li
Journal: Neuro-Oncology (2022)

Abstract Intracranial tumors located in otherwise difficult-to-resect regions of the brain are routinely biopsied to obtain tissue diagnosis and guide clinical decision making. However, tissue yield from these stereotactic biopsy samples is limited and leaves little remaining for research purposes or tumor banking. Given the importance of molecular diagnostics and rise of targeted therapies, research into the genetic and immune landscape of these lesions is of paramount importance, especially for inoperable and deep-seated tumors. We sought to obtain viable cellular material from otherwise discarded biopsy probes without visible tumor sample within the probe. Cells were obtained from clinically challenging pediatric tumors of the brainstem, thalamus, and pineal region by washing biopsy probes in FBS media immediately after completion of a stereotactic biopsy. The wash was then filtered and re-suspended in media before evenly distributing in a 24 well plate for culture purposes. A total of 15 samples were collected from probe washes, including 6 diffuse midline gliomas of the brain stem, 7 supratentorial diffuse midline gliomas, and 2 tumors in the pineal region. Viable tumor cells were obtained from 9/15 samples, ranging from 500 to approximately 525,000 cells per sample wash (219,222 ± 181,951). Orthotopic implantation into matching locations was completed with 7 tumor samples. Formation of a patient-derived orthotopic xenograft was confirmed in one thalamic high-grade glioma (165,000 cells). Three of the five diffuse midline gliomas of the brainstem showed early signs of tumor formation (yielding &amp;gt;2 million cells) and will be validated. In conclusion, viable tumor cells can be collected from biopsy probe washes after stereotactic biopsy, without visible tumor within the probe. Tumor cells can be used for patient-derived orthotopic xenograft tumor formation, which allows for new avenues in the development of animal models of difficult to resect brain tumors.
Establishment of 5-hydroxymethylcytosine expression model of circulating-free DNA gene in early diagnosis of nasopharyngeal carcinoma.
Authors: Bijuan Chen
Journal: Journal of Clinical Oncology (2022)

e18047 Background: Nasopharyngeal carcinoma (NPC) has no obvious symptoms in the early stage of onset, and more than 65% of patients have been diagnosed as intermediate and advanced stage. Studies have shown that early diagnosis and timely treatment of NPC play a key role in the survival of patients.5-hydroxymethylcytosine (5hmC) as an important epigenetic modification of DNA is closely related to gene regulation and NPC pathogenesis. Objective: To clarify the diagnostic value of 5hmC expression in circulating free DNA (cfDNA) gene for NPC. Methods:The expression of 5hmC in cfDNA of 166 NPC and 165 controls was detected with high-throughput technology, and the differentially expressed gene map of 5hmC was drawn. Based on the screened 5hmC Top50 differentially expressed genes, the NPC diagnosis model was established with 70% of the sample size as the training set and 30% as the verification set. The efficacy of 5hmC in distinguishing NPC from healthy controls was evaluated by drawing the receiver operating characteristic curve (ROC) and calculating the sensitivity, specificity, area under the curve (AUC) and accuracy rate (AR). Results: High throughput detection showed that there were significant differences in 5hmC expression of 194 genes between NPC and control cfDNA, of which 185 genes were up-regulated and 9 down regulated in NPC. The results of diagnostic test show that when the Youden index threshold of 0.4749 at the verification set is taken as the cut-off value, the sensitivity, specificity, AUC and AR of the training set are 0.7652, 0.7304, 0.8250 and 0.7478, while in the verification set, they are 0.6863, 0.7400, 0.7388 and 0.7129 respectively. Conclusions: Our findings suggest that cell-free 5hmC signatures are valuable as potential noninvasive diagnostic biomarkers of NPC, which can be transformed into clinical application by further optimizing the diagnostic model.
A randomized phase II/ III trial of nivolumab versus nivolumab plus docetaxel for previously treated advanced or recurrent non–small cell lung cancer: TORG1630.
Authors: Yosuke Kawashima, Yuri Taniguchi, Tsuneo Shimokawa, Yuichi Takiguchi, Toshihiro Misumi, Atsushi Nakamura, Naoki Furuya, Kentaro Tanaka, Toshiyuki Harada, Hisashi Tanaka, Satoru Miura, Masafumi Sata, Terufumi Kato, Takaaki Tokito, Katsuhiko Naoki, Akihiro Bessho, Yasuhiro Goto, Shinji Nakamichi, Hiroaki Okamoto
Journal: Journal of Clinical Oncology (2022)

9030 Background: Immuno-checkpoint inhibitor (ICI) monotherapy is a standard second-line treatment for non-small-cell lung cancer (NSCLC). Addition of a cytotoxic agent to ICI may enhance the benefits. Methods: This multi-institutional open-label randomized phase II/III study compared the arm A consisting of nivolumab (NIV) monotherapy and arm B consisting of NIV + docetaxel (DTX) for patients with previously treated ICI-naïve NSCLC, prestratified by PS/histological types/sex/driver-mutations. The primary endpoint was superiority of arm B in OS in the phase III part. Assuming a HR of 0.75 for OS with the estimated mOS of arm A/B as 10.5/14.0 mo, a total 350 patients would be required to provide 80% power at a one-sided α of significance being 0.05. It was started at Nov. 2017, however, the patients’ accrual was discontinued due to the approval of ICI in the first-line setting in late 2018. Eventually, a total of 131 patients were enrolled for analysis. Results: 128 patients (64 in each arm) were eligible and included in full analysis set (FAS), and the patients’ demographics were well-balanced in each arm. The mOS was 14.7 mo (95%CI, 11.4-18.7) in arm A, and 23.1 mo (95%CI, 16.7-NR) in arm B. The HR of OS was 0.63 (90%CI, 0.42-0.95; p = 0.0310). The mPFS was 3.1 mo (95%CI, 2.0-3.9) and 6.7 mo (95%CI, 3.8-9.4) in arm A and B, respectively. The HR for PFS was 0.58 (95%CI, 0.39-0.88; p = 0.0095). The ORR was 14.0% (95%CI, 6.3-25.8) in arm A, and 41.8% (95%CI, 28.7-55.9) in arm B, with a statistical significance (p = 0.0014). Subgroup analyses for OS disclosed that the HRs favored arm B over arm A across all prespecified subgroups. The mOS of EGFR-mutant subgroup also showed better tendency in arm B than A (11.0 mo in arm A; 95%CI, 3.5-14.0; vs 20.6 mo in B; 95%CI, 5.8-NR; HR 0.45; 95%CI, 0.17-1.17). The hematological toxicity and gastrointestinal adverse events were more common in arm B than in A. Six (9.4%) in arm A and 25 patients (39.1%) in arm B discontinued protocol treatment due to adverse events. Overall, two treatment-related deaths were observed; one from pneumonitis in arm A, and one from myocarditis in arm B. Conclusions: Although the resulting statistical power was limited because of reduced sample size, the addition of DTX to NIV in the second-line NSCLC therapy significantly improved OS, PFS, and ORR, despite slightly elevated risk of toxicity. This is the first randomized clinical trial that confirmed significant survival benefit of ICI + chemotherapy over ICI alone in any cancer type. Clinical trial information: UMIN000021813.
Quality-adjusted time without symptoms or toxicities (Q-TWiST) analysis of ZUMA-7, a randomized controlled trial of axicabtagene ciloleucel versus standard of care for second-line large B-cell lymphoma.
Authors: Marie José Kersten, Yao Qiao, Ruchit Shah, Caitlyn Solem, Julia Snider, Christina Ann To, Paul Cheng, Clare Spooner, Miguel-Angel Perales
Journal: Journal of Clinical Oncology (2022)

7555 Background: Quality of life (QoL) post cancer therapy is increasingly important. We conducted a Q-TWiST analysis to compare the quality-adjusted survival of axicabtagene ciloleucel (axi-cel, a chimeric antigen receptor T-cell therapy) versus standard of care (SOC) among relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients enrolled in ZUMA-7 (NCT03391466), a Phase 3, randomized, open-label, multicenter study. ZUMA-7 met its primary endpoint of event-free survival; events were defined as death, progression, or new lymphoma therapy. Methods: Overall survival (OS) in the intention-to-treat (ITT) cohort was partitioned into 3 mutually exclusive health states as measured through a median follow-up duration of 23.5 months (m): time with grade 3/4 adverse events (AE) before an event (TOX); time without symptoms from events or toxicity (TWiST); and time after event (REL). Q-TWiST was calculated as the average time spent in each state, weighted by state-specific QoL utility (u, ranging from 0 to 1), assuming a base case u(TOX)=0.5, u(REL)=0.5, u(TWiST)=1. Threshold analyses assessed the mean Q-TWiST differences between axi-cel and SOC by varying u(TOX) and u(REL) from 0 to 1. Relative gains for axi-cel (axi-cel Q-TWIST gain divided by mean SOC OS) ≥15% were considered “clearly clinically important” using published norms. Nonparametric bootstrap 95% confidence intervals (CI) were computed. Subgroup analyses were performed for relapse status and age. Sensitivity analyses varying the follow-up duration from 3 to 37.7m were explored. Results: For the ITT cohort (n=359), mean time spent in TOX and TWiST was significantly longer for the axi-cel cohort compared to SOC, and mean time spent in REL was significantly shorter for axi-cel (Table). Using the base case, quality-adjusted survival was significantly longer for axi-cel by 3.7m, representing a 21.9% relative gain. In threshold analyses, the difference in Q-TWiST ranged from 1.2m (u(TOX)=0, u(REL)=1) to 6.2m (u(TOX)=1, u(REL)=0) in favor of axi-cel. Q-TWiST gains favored axi-cel across all subgroup analyses. Q-TWiST gains from axi-cel increased with longer follow-up. Conclusions: Axi-cel was associated with statistically significant and “clearly clinically important” gains in quality-adjusted OS vs. SOC in R/R LBCL, regardless of the relative decline in QoL associated with treatment toxicity, disease progression, or additional cancer treatment.[Table: see text]
A phase II study combining KN046 (an anti-PD-L1/CTLA-4 bispecific antibody) and lenvatinib in the treatment for advanced unresectable or metastatic hepatocellular carcinoma (HCC): Updated efficacy and safety results.
Authors: Baocai Xing, Xu Da, Yanqiao Zhang, Yue Ma
Journal: Journal of Clinical Oncology (2022)

4115 Background: PD-1 inhibitor with Lenvatinib were reported to improve ORR in patients with metastatic HCC. KN046 was a bispecific antibody that target both PD-1/PD-L1 and CTLA-4/B7 immune checkpoints pathway. Preliminary report already showed good efficacy and tolerable safety of the KN046+Lenvatinib regimen. Here we updated the efficacy and safety results with more enrolled patients and longer follow-up duration. Methods: This is an open-label, single-arm, multicenter, phase II trial in pts with unresectable or metastatic HCC. Enrolled patients (pts) with Barcelona Clinic Liver Cancer (BCLC) stage B or C who were not suitable for curative surgery or local therapy had received Lenvatinib 12 mg/day (bodyweight [BW] ≥60 kg) or 8 mg/day (BW&lt;60 kg) orally and KN046 5 mg IV on Day 1 of a 21-day cycle until disease progression or intolerable toxicity or 2-year treatment. Primary endpoints were safety and ORR by RECISTv1.1 per investigators. Results: As data cutoff (January 7, 2022) date, 55 enrolled pts received combination treatment with median duration of 25 weeks. For 52 evaluable pts, ORR was 51.9% (95% CI 37.6-66.0) (RECIST v1.1) and DCR was 86.5% (95% CI 74.2-94.4) (RECIST v1.1). Median PFS was 9.3 months (95% CI 7.0–not estimable [NE]), The median OS and DOR of pts were not reached. The overall incidence of KN046 related treatment-emergent adverse events(TRAEs) was 98.2%, with 27.3% Gr3. The most common Grade ≥ 3 TRAEs included platelet count decreased (7.3% of pts) and aspartate aminotransferase increased (3.6% of pts). The immune related adverse events (irAE) occurred in 14.5% of pts (grade ≥3 5.5%). 3 pts discontinued KN046 treatment due to ≥3 Gr TRAE, which was infusion related reaction, platelet count decreased and interstitial lung disease. 4 (7.2%) pts died from KN046 TRAEs (Hyponatremia, n=1; Interstitial lung disease, n=2; Cause of death unknown, n=1). Conclusions: KN046+Lenvatinib demonstrated a promising efficacy in ORR and PFS and the manageable safety profile in the first-line advanced unresectable or metastatic HCC treatment. These result support the KN046 plus Lenvatinib as a potential new treatment option for this population. Clinical trial information: NCT04542837.
Oncolytic virus expressing PD-1 inhibitors activates a collaborative intratumoral immune response to control tumor and synergizes with CTLA-4 or TIM-3 blockade
Authors: Fei Ju, Yong Luo, Chaolong Lin, Xian Jia, Zilong Xu, Rui Tian, Yanhua Lin, Min Zhao, Yating Chang, Xiaoxuan Huang, Shaopeng Li, Wenfeng Ren, Yaning Qin, Mengqin Yu, Jizong Jia, Jinle Han, Wenxin Luo, Jun Zhang, Guo Fu, Xiangzhong Ye, Chenghao Huang, Ningshao Xia
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Oncolytic viruses (OVs) are capable to inflame the tumor microenvironment (TME) and elicit infiltrating tumor-specific T cell responses. However, OV treatment negatively alters the cancer-immune set point in tumors to attenuate the antitumor immune response, which suggests the necessity of dissecting the immune landscape of the virus-treated tumors and developing novel strategies to maximize the potential of OVs. The aim of this study is to investigate the effect of the single-chain variable fragment (scFv)-armed OVs targeting PD-1 on the TME, and ultimately overcome localized immunosuppression to sensitize tumors to immunotherapies. Methods A tumor-selective oncolytic herpes simplex virus vector was engineered to encode a humanized scFv against human PD-1 (hPD-1scFv) (YST-OVH). The antitumor efficacy of YST-OVH was explored in multiple therapeutic mouse models. The neurotoxicity and safety of YST-OVH were evaluated in nonhuman primates. The precise dynamics in the TME involved in YST-OVH treatment were dissected using cytometry by time-of-flight (CyTOF). Results The identified hPD-1scFv showed superior T-cell activating activity. Localized delivery of hPD-1scFv by YST-OVH promotes systemic antitumor immunity in humanized PD-1 mouse models of established cancer. Immune profiling of tumors using CyTOF revealed the enhanced antitumor effect of YST-OVH, which largely relied on CD8 + T cell activity by augmenting the tumor infiltration of effector CD8 + T cells and establishment of memory CD8 + T cells and reducing associated CD8 + T cell exhaustion. Furthermore, YST-OVH treatment modified the cancer-immune set point of tumors coupled to coexpression of CTLA-4 and TIM-3 on exhausted CD8 + T cells and high levels of CTLA-4 + Treg cells. A combination approach incorporating anti-CTLA-4 or anti-TIM-3 further improved efficacy by increasing tumor immunogenicity and activating antitumor adaptive immune responses. Moreover, this therapeutic strategy showed no neurotoxicity and was well tolerated in nonhuman primates. The benefit of intratumoral hPD-1scFv expression was also observed in humanized mice bearing human cancer cells. Conclusion Localized delivery of PD-1 inhibitors by engineered YST-OVH was a highly effective and safe strategy for cancer immunotherapy. YST-OVH also synergized with CTLA-4 or TIM-3 blockade to enhance the immune response to cancer. These data provide a strong rationale for further clinical evaluation of this novel therapeutic approach.
Worldwide survey on the current practice of asymptomatic urinary stone management: A survey from EAU, Young Academic Urologists (YAU), Endourology and Urolithiasis Working Party
Authors: T.E. Şener, T. Tailly, A. Pietropaolo, E.X. Keller, Y. Tanidir, J.G. Rivas, Z. Hameed, V. De Coninck, T. Tefik, K. Sarica, A.S. Gozen, A. Skolarikos, O. Traxer, B. Somani
Journal: European Urology (2022)